Improved process for the 5{60 ,6{60 -epoxidation of {66 {11 -double bonds

ABSTRACT

An improved process for the stereoselective 5 Alpha ,6 Alpha epoxidation of isolated 5,6-double bonds in steroid molecules. The process of this invention comprises reacting a steroid containing an isolated 5,6-double bond with peroxytrifluoroacetic acid or peroxytrichloroacetic acid in an organic solvent of low polarity which promotes intramolecular hydrogen bonding in the peracid molecule, and in the presence of a basic buffering agent, to obtain the corresponding 5 Alpha ,6 Alpha -epoxide. An important characteristic of many pharmacologically active steroids is the presence of a methyl or halogen substituent at the 6 Alpha -position. The process of this invention provides an improved method for obtaining important 5 Alpha ,6 Alpha expoxide intermediates leading to these useful compounds.

United States Patent Parikh 51 July 11, 1972 [54] IMPROVED PROCESS FORTHE 5a,6a-

EPOXIDATION OF A -DOUBLE BONDS 72 Inventor: Jekishan R. Parlkh,Kalamazoo, Mich.

[73] Assignee: The Upjohn Company, Kalamazoo, Mich. [22] Filed: Sept.15, 1970 [21] Appl.N0.: 72,490

[52] US. Cl. ..260/239.55 R, 260/239.55 C, 260/3975 Spero et al., J. Am.Chem. Soc. Vol. 78 (1956) page 6213 Primary Examiner-Elbert L. RobertsAttorney-John Kekich and Ward F. Nixon [57] ABSTRACT An improved processfor the stereoselective 5a,6a-epoxidation of isolated 5,6-double bondsin steroid molecules. The process of this invention comprises reacting asteroid containing an isolated 5,6-double bond withperoxytrifluoroacetic acid or peroxytrichloroacetic acid in an organicsolvent of low polarity which promotes intramolecular hydrogen bondingin the peracid molecule, and in the presence of a basic buffering agent,to obtain the corresponding 5a,6a-epoxide.

An important characteristic of many pharmacologically active steroids isthe presence of a methyl or halogen substituent at the a-position. Theprocess of this invention provides an improved method for obtainingimportant 5a,6a-expoxide intermediates leading to these usefulcompounds.

11 Claims, No Drawings PROCESS FOR THE a,6a-EPOXIDATION OF A -DOUBLEBONDS BACKGROUND OF THE INVENTION The epoxidation of steroidal5,6-double bonds is well known in the art, for example, G. Cooley eta.l., J. Chem. Soc. 4112 (1957); G. B. Spero et al., J. Am. Chem. Soc.78, 6213 (1956); J. C. Babcock et al., J. Am. Chem. Soc. 80, 2904(1958); Camerino et al., US. Pat. No. 3,061,616 and George B. Spero, US.Pat. No. 3,377,364. The above mentioned prior art shows the epoxidationof certain A -steroids using common organic peracids such as peracetic,perbenzoic, perpropionic, monoperphthalic, and performic acids to obtaina mixture of the corresponding 5a,6aand 5B,6B-epoxides. The reactionsare carried out in an inert organic solvent such as chloroform,methylene chloride, ethylene dichloride, carbon tetrachloride, benzene,toluene, diethyl ether, mixtures thereof and the like.

The prior art epoxidation processes using well-known peracids such asthose mentioned above are not stereo-selective and give mixtures of boththe desired corresponding 5a,6a-epoxide and the undesired corresponding5B,6fl-epoxide in ratios ranging from about 50:50 to a maximum of about70:30. For example, lla-acetoxy-5-pregnene-3,20dione 3 ,20-bisethyleneketal when epoxidized using peracetic acid in chlorobenzene, chloroform,or mixtures thereof in accordance with the prior art process of Spero etal., J. Am. Chem. Soc., 78, 6213 (1956), gives at best only about a 61percent theoretical yield of the desired5a,6a-epoxy-1laacetoxypregnane-3 ,20-dione 3 ,20-bisethylene ketal.

The in situ formation of peroxytrifluoroacetic acid, prepared by theaddition of trifluoroacetic acid to hydrogen peroxide, and its uniqueproperty as an oxidizing agent were first described by W. D. Emmons andA. F. Ferris, J. Am. Chem. Soc. 75, 4623 (1953). The utilization ofperoxytrifuoroacetic acid as an epoxidation agent for aliphatic andalicyclic olefins was first reported by W. D. Emmons and A. S. Pagano,J. Am. Chem. Soc. 77, 89 (1955). The use of peroxytrihaloacetic acids,for the stereoselective epoxidation of double bonds in steroidalmolecules has not hitherto been known and, in addition, the effects ofsolvents on the stereoselective course of the epoxidation with theseacids is also a new and novel part of the present invention.

BRIEF SUMMARY OF THE INVENTION Steroids containing the 5a,6a-epoxidefunction are important intermediates in the synthesis of 6-alkyl an'd6-halosteroids such as Medrol (6a-methylprednisolone), Melenges-trolacetate l6-methylenel 7a-acetoxy-6-methyl-4,6- pregnadiene-3,20-dione),Provera (6a-methyl-l7a-acetoxyproges-terone), Alphadrol(Ga-fluoroprednisolone), Haldrone (6a-fluoro- 1 a-methyl-l 113, 1 711,21 -trihydroxyl ,4- pregnadiene-3,20-dione ZI-acetate) and many otherswell known in the art.

In the process for epoxidizing isolated 5,6-double bonds in the steroidmolecule with an organic peracid, it has now been discovered thatgreatly increased yields (greater than 90 percent of theory) of thedesired 5a,6a-epoxide can be obtained with very little formation of theundesirable corresponding 5B,6B-epoxide. The high yields of the desired5a,6a-epoxides obtained by the process of this invention are broughtabout by epoxidizing a A -steroid with peroxytrifluoroacetic acid orperoxytrichloroacetic acid in an organic solvent of low polarity whichpromotes intramolecular hydrogen bonding within the peracid molecule,The reaction is carried out in the presence of a basic buffering agentto prevent decomposition of acid sensitive substrates, for example, toprevent hydrolysis of 3- and -ketal groups when present in the startingmaterial and to prevent opening of the oxirane ring.

DETAILED DESCRIPTION OF THE INVENTION The improved process of thisinvention is generally applicable to any steroid having an isolated(unconjugated) double bond at the 5,6-position of the steroid molecule.They can also possess keto, hydroxy, alkyl, acyloxy, halo, cyclopropyl,cyclic alkylene ketal and other groups attached to the steroid ringstructure, especially at positions 3, 4, 7, 9, l 1, 12, 14, 16, 17, 20,and 21 and they can have other double bonds which are unreactive underthe conditions of the process of the present invention.

In carrying out the improved process of this invention, the selectedstarting steroid having an unconjugated double bond at the 5,6-positionis dissolved, dispersed or suspended in an organic solvent compatiblewith. the stereo-selective formation of the desired 5a,6a-epoxide of theselected starting material. Organic solvents which are stereoselectiveto 5a,6a-epoxide formation are those of low polarity which promoteintramolecular hydrogen bonding within the selected peracid molecule.The following solvents are representative of those which can be used,for example, methylene chloride, benzene, chlorobenzene, toluene,chloroform, bromobenzene, odichlorobenzene, xylene, ethylene dichloride,mixtures thereof and the like. A basic buffering agent is added and thereaction mixture is cooled to a temperature below 0 C.; -l0 C. to -30 C.is preferred. The mixture is then treated with a solution ofperoxytrifluoroacetic acid or peroxytrichloroacetic acid (prepared insitu in an organic solvent medium of low polarity which promotesintramolecular hydrogen bonding within the selected peracid). Thetemperature is maintained below 0 C. during the peracid addition andpreferrably within the range of from about -10 to about 30 C. Basicbuffering agents which can be used include, for example, sodium acetate,potassium acetate, sodium carbonate, potassium carbonate, sodiumbicarbonate, potassium bicarbonate, disodium hydrogen phosphate, etc.When the reaction is complete the 5a,6a-epoxide is recovered from thereaction medium by conventional methods, for example, the reactionmixture is made basic by the addition of dilute sodium or potassiumhydroxide, the organic phase is separated from the aqueous phase, washedto a neutral pH, filtered and then removed by distillation to give thedesired 5a,6a-epoxide. The epoxide thus obtained is further purified ifdesired by crystallization from a suitable organic solvent such asacetone, acetone-water, ether, ethyl acetate, methylene chloride,benzene and the like.

The following preparations and examples further illustrate the processof this invention but are not to be construed as limiting.

Preparation 1 peroxytriiluoroacetic acid A solution of 8.5 ml. oftrifluoroacetic anhydride in 10 ml. of methylene chloride is cooled toabout 0 C. and 2 ml. of percent hydrogen peroxide is added. The solutionis stirred at 0 C. for about 15 minutes and then allowed to reach roomtemperature. For storage purposes the solution of peroxytrifluoroaceticacid, thus obtained, is kept at or below 0 C.

Preparation 2 peroxytrichloroacetic acid A solution of 9.0 ml. oftrichloroacetic anhydride in 10 ml. of methylene chloride is cooled to 0C. and treated with 90 percent hydrogen peroxide in the manner describedin Preparation 1, above, to obtain a solution of peroxytrichloroaceticacid. For storage purposes the solution is advantageously kept at about0 C. or below.

Example 1 5a,6a-epoxy-l la-acetoxypregnane-B,20-dione 3,20-bisethyleneketal A reaction mixture of 9.2 g. (0.02 moles) of 1 la-acetoxy-S-pregnene-3,20-dione 3,20-bisethylene ketal, 19.6 g. (0.2 moles) ofanhydrous potassium acetate, 52 ml. of chloroform (dry) and 52 ml. ofchlorobenzene (dry) is cooled to about 20 C. stirring. The solution ofperoxytrifluoroacetic acid prepared in Preparation 1 above, is dilutedwith ml. of methylene chloride, cooled to about -20 C. and added slowlyto the reaction mixture while maintaining the temperature at about -20C. The progress of the reaction is followed by thin layer chromatography(TLC).

When the reaction is complete, the reaction mixture is made basic by theaddition of dilute sodium hydroxide solution to a pH of about 9 andstirred for about 1 hour at l2-l 4 C. The organic phase is thenseparated and washed to a neutral pH. Each aqueous wash is back washedwith chloroform and the chloroform is added to the organic phase. Thecombined organic phase and washes are stirred with 0.3 g. ofdiatomaceous earth (Celite), filtered and the filter cake is washed withthree 5 ml. portions of chloroform. The filtrate and washes are combinedand concentrated to dryness under vacuum at about 60 C. to give 9.2 g.(96.6 percent yield) of 5a,6aepoxy-l la-acetoxypregnane-3,ZO-dione 3,20-bisethylene ketal; m.p. 248-260 C.; [(11 59.

To 3.0 g. of the a,6a-epoxide thus obtained, is added 6 ml. of ethylacetate. The slurry so obtained is stirred under reflux for about 1hour, cooled to C. and stirred at 15 C. for 2 hours. The slurry isfiltered, washed with a minimum of cold ethyl acetate and dried to give2.88 g. (92.8 percent yield) of 5a,6a-epoxy-lla-acetoxypregnane-3,20-dione 3,20- bisethylene ketal; m.p. 260.5262.5C.; [01],, -62; TLC shows one spot, NMR is consistent with the structureand identical to that of a standard sample of the same product.

Example 2 5a,6a-epoxypregnane-3,20-dione 3,20-bisethylene ketal Areaction mixture of8 g. (0.02 moles) of 5-pregnene-3,20- dione3,20-bisethylene ketal, 19.6 g. (0.2 moles) of anhydrous potassiumacetate, 52 ml. of chloroform (dry) and 52 ml. of chlorobenzene (dry) iscooled to about C. with stirring. The solution of peroxytrifluoroaceticacid prepared in Preparation 1, above, is diluted with 100 ml. ofmethylene chloride, cooled to about 20 C. and added slowly to thereaction mixture while maintaining the temperature at about 20 C. Theprogress of the reaction is followed by thin layer chromatography (TLC).

When the reaction is complete, the reaction mixture is made basic by theaddition of dilute sodium hydroxide solution to a pH of about 9 andstirred for about 1 hour at l2-l4 C. The organic phase is then separatedand washed to a neutral pH. Each aqueous wash is back washed withchloroform and the chloroform is added to the organic phase. Thecombined organic phase and washes are stirred with 0.3 g. ofdiatomaceous earth (Celite), filtered and the filter cake is washed withthree 5 ml. portions of chloroform. The filtrate and washes are combinedand concentrated to dryness under vacuum at about 60 C. to give 8.14 g.(97.2 percent yield) of 5a,6a-epoxypregnane-3,20-dione-3,20-bisethyleneketal; NMR analysis of the product showed the presence of less than 5percent of the corresponding 513,6B-epoxide. An analytical sampleprepared by chromatography gave Saba-epoxypregnane-3,20-dione3,20-bisethylene ketal; m.p. l80.5l 83 C.; [a],, 50.

Example 3: 5a,6a-epoxy-1 lfl-hydroxypregnane-3,20-dione 3,20-bisethyleneketal A reaction mixture of 4.2 g. (0.01 moles) of l lB-hydroxy-S-pregnene-3,20-dione 3,20-bisethylene ketal, 9.65 g. (0.1 moles) ofanhydrous potassium acetate, 26 ml. of chloroform (dry) and 26 ml. ofchlorobenzene (dry) is cooled to about -20 C. with stirring. Thesolution of peroxytrifluoroacetic acid prepared in Preparation 1, above,is diluted with 50 ml. of methylene chloride, cooled to about 20 C. andadded slowly to the reaction mixture while maintaining the temperatureat about 20 C. The progress of the reaction is followed by thin layerchromatography (TLC).

When the reaction is complete, the reaction mixture is made basic by theaddition of dilute sodium hydroxide solution to a pH of about 9 andstirred for about 1 hour at l2-l4 C. The organic phase is then separatedand washed to a neutral pH. Each aqueous wash is back washed withchloroform and the chloroform is added to the organic phase. Thecombined organic phase and washes are stirred with 1.5 g.

of diatomaceous earth (Celite), filtered and the filter cake is washedwith three 5 ml. portions of chloroform. The filtrate and washes arecombined and concentrated to dryness under vacuum at about 60 C. to give4.32 g. (99.0 percent yield) of 5a,6a-epoxy-l l fl-hydroxypregnane-3,20-dione 3 ,20- bisethylene ketal; NMR analysis shows the presence ofless than 5 percent of the 5,8,6/3-epoxide. An analytical samplerecrystallized from ethyl acetate gives 5a,6a-epoxy-l 1B-hydroxypregnane-3,20-dione 3,20-bisethylene ketyl; m.p. 255.3-260.3C.;[a] 27; NMR and IR spectra support the structure.

In the same manner following the procedure of Examples 1, 2 and 3analogous results are obtained when a solution of peroxytrichloroaceticacid (prepared in Preparation 2, above) is used in place of a solutionof peroxytrifluoroacetic acid.

Example 4 5a,6a-epoxy-3fl-hydroxyl 6-pregnen-20-one Following theprocedure of Example 1 above, 3fl-hydroxy- 5 ,l6-pregnadien-20-one isepoxidized to obtain 5a,6a-epoxy- 3,8-hydroxyl 6-pregnen-20-one.

Example 5 5a,6a-epoxy-3B-acetoxyl 6-pregnen-20-one Following theprocedure of Example 1 above, 3,8-acetoxy- 5,l6-pregnadien-20-one isepoxidized to obtain 5a,6a-epoxy- 3B-acetoxyl 6-pregnen-20-one.

Example 6 methyl 5a,6a-epoxy-3,l l-diketo-l 7( 20)-pregnen- 2 l-oate3-ethylene ketal Following the procedure of Example 1 above, methyl 3,]ldiketo-5,l7(20)-pregnadien-2l-oate 3-ethylene ketal is epoxidized toobtain methyl 5a,6a-epoxy-3,l l-diketo-l 7(20)- pregnen-2 l-oate3-ethylene ketal.

EXAMPLE 7: 5a,6a-epoxy-l7a-hydroxypregnane-3,20-dione 3,20-bisethyleneketal Following the procedure of Example 1 above, l7a-hydroxy-5-pregnene-3,20-dione 3,20-bisethylene ketal is epoxidized to obtain5a,6a-epoxy-l7a-hydroxypregnane-3,20-dione 3,20- bisethylene ketal.

EXAMPLE 8: 5a,6a-epoxyl 7a-acetoxypregnane-3 ,20-dione 3,20-bisethyleneketal Following the procedure of Example 1 above, l7a-acetoxy-5-pregnene-3,20-dione 3,20-bisethylene ketal is epoxidized to obtain5a,6a-epoxyl 7a-acetoxypregnane-3,20-dione 3 ,20- bisethylene ketal.

EXAMPLE 9: 5a,6a-epoxy-l l B-hydroXy-2 l -acetoxyl 6-pregnene-3,20-dione 3,20-bisethylene ketal Following the procedure ofExample 1 above, 1 IB-hydroxy- 21-acetoxy-5 l 6-pregnadiene-3 ,20-dione3 ,20-bisethylene ketal is epoxidized to obtain 5a,6a-epoxy-llB-hydroxy-Zlacetoxyl 6-pregnene-3,20-dione 3,20-bisethylene ketal.

EXAMPLE l0: 5a,6a-epoxy-l6-pregnene-3,20-dione 3,20- bisethylene ketalFollowing the procedure of Example 1 above, 5,l6- pregnadiene-3,20-dione3,20-bisethylene ketal is epoxidized to obtain5a,6a-epoxy-l6-pregnene-3,20-dione 3,20-bisethylene ketal.

In the same manner following the procedure of Examples 1, 2 and 3 above,other steroids containing an isolated double bond at the 5,6-positioncan be stereoselectively epoxidized with peroxytrifluoroacetic acid orperoxytrichloroacetic acid to obtain the corresponding 5a,6a-epoxide inhigh yield. The following conversions are representative:

5-pregnene-3,20-dione 3,20-bisethylene ketal to obtain5a,6a-epoxypregnane-3,20-dione 3,20-bisethylene ketal;

l7,8-hydroxy-5-androsten-3-one 3-propylene ketal to obtain5a,6a-epoxy-17B-hydroxyandrostan-3-one 3-propylene ketal;

cholesteryl chloride to obtain 3B-chloro-5a,6a-epoxycholestane;

l7a,20;20,2 l -bismethylenedioxy-S-pregnene-3,4-dione 3- ethylene ketalto obtain l7,20;20,2l-bismethylenedioxy-5a,6 a-epoxypregnan-3,l l-dione3-ethylene ketal;

17B-acetoxy-5-androsten-3-one 3-ethy1ene ketal to obtain17B-acetoxy-5a,6a-epoxyandrostan-3-one 3-ethylene ketal;

l7a,2 1 -diacetoxy-5-pregnene-3 ,1 1,2 l -trione 3-ethylene ketal toobtain l701,21-diacetoxy-5a,6a-epoxypregnane- 3,1 1,2 l -trione3-ethylene ketal;

19-nor-5-androstene-3[3,17B-diol diacetate to obtain 19- nor-5a,6a-epoxyandrostane-3/3, l 7B-diol diacetate;

3fl-acetoxy-l7B-cyano-5,16-androstadiene to obtain 511,604- epoxyl7fi-cyanol 6-androstene-3B-ol acetate; and

A -cholestene to obtain cholestane 5a,6a-epoxide.

I claim:

1. In the process for the epoxidation of an isolated 5,6-double bond ina steroid molecule having a ketal derivative of a ketone group at the3-position with an organic peracid to obtain the corresponding5a,6a-epoxide, the improvement which comprises carrying out the reactionwith peroxytrifluoroacetic acid or peroxytrichloroacetic acid in anorganic solvent medium of low polarity which promotes intramolecularhydrogen bonding within the peracid molecule and in the presence of abasic buffering agent.

2. The process for the stereoselective 5a,6a-epoxidation of an isolated5,6-double bond in a steroid molecule having a ketal derivative of aketone group at the 3-position: which comprises subjecting said steroidto epoxidation with peroxytrifiuoroacetic acid or peroxytrichloroaceticacid in an organic solvent medium of low polarity which promotesintramolecular hydrogen bonding within the peracid molecule and in thepresence of a basic buffering agent to obtain the corresponding5a,6a-epoxide.

3. The process of claim 2, wherein the organic solvent is selected fromthe group consisting of methylene chloride, benzene, chlorobenzene,toluene, chloroform,

bromobenzene, o-dichlorobenzene, dichloride and mixtures thereof.

4. The process of claim 2, wherein the starting steroid is1la-acetoxy-5-pregnene-3,20-dione 3,20-bisethylene ketal and the5a,6a-epoxide obtained is 5a,6a-epoxy-l la-acetoxypregnane-3,20-dione3,20-bisethylene ketal.

5. The process of claim 2, wherein the starting steroid is 5-pregnene-3,20-dione 3,20-bisethylene ketal and the 501,601- epoxideobtained is 5a,6a-epoxypregnane-3,20-dione 3,20- bisethylene ketal.

6. The process of claim 2, wherein the starting steroid isl1B-hydroxy-5-pregnene-3,20-dione 3,20-bisethylene ketal and the5oz,6a-epoxide obtained is 5a,6a-epoxy-l1fl-hydroxypregnane-3,20-dione3,20-bisethylene ketal.

7. The process of claim 2, wherein the starting steroid is methyl3,11-diketo-5,17(20)-pregnadien-2l-oate 3-ethylene ketal and the5a,6a-epoxide obtained is methyl 5a,6a-epoxy- 3,1 l-diketol 7(20)-pregnen-2 l-oate 3-ethylene ketal.

8. The process of claim 2, wherein the starting steroid is17a-hydroxy-5-pregnene-3,20dione 3,20-bisethylene ketal and the5a,6a-epoxide obtained is 5a,6a-epoxy-l7a-hydroxypregnane-3,20-dione3,20-bisethylene ketal.

9. The process of claim 2, wherein the starting steroid isl7a-acetoxy-5-pregnene-3,20-dione 3,20-bisethylene ketal and the5a,6a-epoxide obtained is 5a,6a-epoxy-l7a-acetoxypregnane-3,20-dione3,20-bisethylene ketal.

10. The process of claim 2, wherein the starting steroid is llB-hydroxy-21-acetoxy-5 l 6-pregnadiene-3 ,20-dione 3 ,20- bisethyleneketal and the 5a,6u-epoxide obtained is 5a,6aepoxy-1 1B-hydroxy-2l-acetoxyl 6-pregnene-3 ,20-dione 3,20-bisethylene ketal.

11. The process of claim 2, wherein the starting steroid is5,16-pregnadiene-3,20-dione 3,20-bisethylene ketal and the 5a,6a-epoxideobtained is 5a,6a-epoxy-l6-pregnene-3,20- dione 3,20-bisethylene ketal.

xylene, ethylene

2. The process for the stereoselective 5 Alpha ,6 Alpha -epoxidation ofan isolated 5,6-double bond in a steroid molecule having a ketalderivative of a ketone group at the 3-position: which comprisessubjecting said steroid to epoxidation with peroxytrifluoroacetic acidor peroxytrichloroacetic acid in an organic solvent medium of lowpolarity which promotes intramolecular hydrogen bonding within theperacid molecule and in the presence of a basic buffering agent toobtain the corresponding 5 Alpha ,6 Alpha -epoxide.
 3. The process ofclaim 2, wherein the organic solvent is selected from the groupconsisting of methylene chloride, benzene, chlorobenzene, toluene,chloroform, bromobenzene, o-dichlorobenzene, xylene, ethylene dichlorideand mixtures thereof.
 4. The process of claim 2, wherein the startingsteroid is 11 Alpha -acetoxy-5-pregnene-3,20-dione 3,20-bisethyleneketal and the 5 Alpha ,6 Alpha -epoxide obtained is 5 Alpha ,6 Alpha-epoxy-11 Alpha -acetoxypregnane-3,20-dione 3,20-bisethylene ketal. 5.The process of claim 2, wherein the starting steroid is5-pregnene-3,20-dione 3,20-bisethylene ketal and the 5 Alpha ,6 Alpha-epoxide obtained is 5 Alpha ,6 Alpha -epoxypregnane-3,20-dione3,20-bisethylene ketal.
 6. The process of claim 2, wherein the startingsteroid is 11 Beta -hydroxy-5-pregnene-3,20-dione 3,20-bisethylene ketaland the 5 Alpha ,6 Alpha -epoxide obtained is 5 Alpha ,6 Alpha -epoxy-11Beta -hydroxypregnane-3,20-dione 3,20-bisethylene ketal.
 7. The processof claim 2, wherein the starting steroid is methyl3,11-diketo-5,17(20)-pregnadien-21-oate 3-ethylene ketal and the 5 Alpha,6 Alpha -epoxide obtained is methyl 5 Alpha ,6 Alpha-epoxy-3,11-diketo-17(20)-pregnen-21-oate 3-ethylene ketal.
 8. Theprocess of claim 2, wherein the starting steroid is 17 Alpha-hydroxy-5-pregnene-3,20-dione 3,20-bisethylene ketal and the 5 Alpha ,6Alpha -epoxide obtained is 5 Alpha ,6 Alpha -epoxy-17 Alpha-hydroxypregnane-3,20-dione 3,20-bisethylene ketal.
 9. The process ofclaim 2, wherein the starting steroid is 17 Alpha-acetoxy-5-pregnene-3,20-dione 3,20-bisethylene ketal and the 5 Alpha ,6Alpha -epoxide obtained is 5 Alpha ,6 Alpha -epoxy-17 Alpha-acetoxypregnane-3,20-dione 3,20-bisethylene ketal.
 10. The process ofclaim 2, wherein the starting steroid is 11 Beta-hydroxy-21-acetoxy-5,16-pregnadiene-3,20-dione 3,20-bisethylene ketaland the 5 Alpha ,6 Alpha -epoxide obtained is 5 Alpha ,6 Alpha -epoxy-11Beta -hydroxy-21-acetoxy-16-pregnene-3,20-dione 3,20-bisethylene ketal.11. The process of claim 2, wherein the starting steroid is 5,16-pregnadiene-3,20-dione 3,20-bisethylene ketal and the 5 Alpha ,6Alpha -epoxide obtained is 5 Alpha ,6 Alpha-epoxy-16-pregnene-3,20-dione 3,20-bisethylene ketal.